Systems Biology Wiki
Why understanding an entire system is important. Systems biology attempts to explore biological structures in an all-inclusive manner, with data input from all cellular levels previously explored by ‘omics’ studies. The question remains, what is the relevance to this type of understanding of an entire system? Introduction Joanne Brodie Systems biology describes a field of study which explores the structure and dynamics of cellular function. Many people believe the idea of systems biology to be relatively recent and emerging but it is merely a product of molecular biology that has outgrown its synonymous existence with studies of molecular genetics Westerhoff, H.V., Alberghina, L. (2005). ‘Systems Biology: Did we know it all along?’, Topics in Current Genetics, 13, pp. 3-9.. Since the discovery of DNA the arrival of genomics has contributed to a successive submergence of scientific research; the primary focus of which delves into understanding how cell functions and responses are a consequence of complex cellular processes. These ‘omics’ represent a top-down attitude to systems biology research and are essentially focused on the discovery of new molecular mechanisms which correlate the concentrations of molecules in cells with hypotheses formulated to explain the processes regulating these concentrations in the cell Bruggeman, F. J., Westerhoff, H. V. (2007) ‘The Nature of Systems Biology’, TRENDS in Microbiology, 51, pp. 45-50.. The emerging branch of systems biology is one focused on a bottom-up approach, looking at the large number of interactions which comprise living cells to produce their distinct genotype, and eventually phenotype Kitano, H. (2002) ‘Systems Biology: A Brief Overview’. Science (295) pp. 1662-1664.. Overall this branch of study looks at living organisms as displays of an entire system working as one interacting network of molecular components, as opposed to products of individual reactions. To accomplish such studies mathematical models using high-throughput, quantitative experimental approaches are used to collect data for observation and interpretation of system network dynamics. Computer simulations can then be configured to comprehend behavioural outcomes of entire living organisms, not just for specific cells or reactions Westerhoff, H. V., Palsson, B. O. (2004) ‘The evolution of molecular biology into systems biology’, Nature Biotechnology, 22, pp. 1249-1252.. The main aim ultimately being to be able to calculate how a living system will function, which could be applied to understanding of genetic abnormalities, the effect they will have on a system and how this could be remedied if necessary. It is the vision of Dr. Leroy Hood, co-founder and president of the Institute for Systems Biology, that in the future healthcare will not just be based on prescriptions adapted to one’s physical state of infirmity, but instead given to prevent disease even occurring Dr Leroy Hood, The Economist, Q3, 15th Sep 2005. ‘Medicine without frontiers’. Available at: http://www.economist.com/node/4368242. Accessed 25/04/2012.. History Lisa Buddrus Although it may seem as though the systems approach is a novel idea of the 20th/21st century, it actually is as ancient as science itself. Already, Aristotle (384-322 B.C.) stated ‘the whole is something over and above its parts and not just the sum of them’ Aristotle (1946) ‘The Politics (translated)’, E. Baker. Oxford, UK: Oxford University Press.. However, in the 17th century a reductionist approach took hold of the developing science of biology. Although reductionisms and holism are often seen as opposites, there is a need to utilize both lines of approach and their ability to answer different questions in order to fully understand an organism Trewavas, A. (2006) ‘A Brief History of Systems Biology’, The Plant Cell, 18, pp. 2420-2430.. Systems analysis has historically been part of many biology areas, such as ecology, immunology and developmental biology. However, in molecular biology it was not necessary to use quantification and sophisticated mathematical models in order to understand how life works Way, J.C., Silver, P.A. (2007) ‘Systems Enegineering Without an Engineer: Why We Need Systems Biology’, Wiley InterScience, 13(2), pp. 22-29.. The roots of systems biology lie in the holistic approach to organisms as a system developed in the 20th century. According to Denis Noble, Claude Bernard was the first system biologist Saks, V., Monge, C., Guzun, R. (2009) ‘Philosophical Basis and Some Historical Aspects of Systems Biology: From Hegel to Noble – Applications for Bioenergetic Research’, Int. J. Mol. Sci., 10(3), pp. 1161-1192.. He developed the theory of the permanence of homeostasis (milieu intérieur) in the 1800s, using an integrative approach to the cell. Some other pioneers were Norbert Wiener with the mathematical theory of communication and control of systems through regulatory feedback, i.e. cybernetics in 1948 Wiener, N. (1948) ‘Cybernetics or the Control and Communication in The Animal and The Machine’, New York: John Wiley & Sons, Inc., and Ludwig von Bertalanffy with the formulation of the general systems theory in 1969 Von Bertalanffy, L. (1969) ‘General Systems Theory: Foundations, Development, Applications’ New York: George Braziller Inc.. The action potential along neuronal axons was one of the first numerical simulations in biology, published in 1952 Hodgkin, A.L., Huxley, A.F. (1952) ‘A quantitative description of membrane current and its application to conduction and excitation in nerve’, Journal of Physiology, 117(4), pp. 500-544.. In 1966 systems biology was formally launched at the international symposium in Cleveland, USA Mesarovic, M.D. (1968) ‘Systems Theory and Biology’, Berlin: Springer Verlag.. The 60s and 70s then saw the development of analysis methods, such as metabolic control analysis, to study complex molecular systems. In the 90s, with the birth of functional genomics, systems biology started to undergo enormous expansion. The first quantitative model of the metabolism of a (hypothetical) cell was published in 1999, the E-cell software Tomita, M., Hashimoto, K., Takahashi, K., Shimizu, T.S., Matsuzaki, Y., Miyoshi, F., Saito, K., Tanida, S., Yugi, K., Venter, J.C., Hutchinson Ill, C.A. (1999) ‘E-CELL: Software Environment for Whole Cell Simulation’, Bioinformatics 15(1), pp.72-84.. The completion of various genome projects and the large increase of data from the 'omics', as well as advances in high-throughput experiments and bioinformatics pushed research forward and caused molecular biology to evolve into systems biology (Fig. 1) . The 21st century saw systems biology research centers opening around the world. In 2006 the National Science Foundation (NSF) put a grand challenge forward – to build a mathematical model of the whole cell Omenn, G.S. (2006) ‘Grand Challenges and Great Opportunities in Science, Technology and Public Policy’, Science, 341(5806), pp. 1696-1704.. The rapid expansion of systems biology becomes clear when a PubMed search results in nearly 2,500 publications this year alone. Westerhoff, H.V., Palsson, B.O. (2004) ‘The evolution of molecular biology into systems biology’, Nature Biotechnology, 22(10), pp. 1249-1252. Associated Diciplines Joanne Brodie Systems biology has developed from a top-down approach of understanding cellular functions. Four main disciplines to this approach are genomics, transcriptomics, proteomics and metabolomics. Studies into these areas have been carried out extensively since the sequencing of entire genomes; as a result there are vast collections of data on DNA, RNA, proteins and metabolites and macromolecules in cellular processes Moreno-Risueno, M. A., Busch, W., Benfey, P. N. (2010) ‘Omics meet networks - using systems approaches to infer regulatory networks in plants’, Current Opinions in Plant Biology, 2, pp. 126-131.. Genomics can be defined as the study of the complete genetic make-up of an organism. Transcriptomics examines the next level of cellular control responsible for the dynamic response (output) produced by cells. At the proteomics level, studies are focused on the structure and function of proteins; this could look at enzymes for example, which alone have an extremely large scope for study. The subsequent level to be examined is then metabolomics which looks at resultant metabolites and macromolecules from the proteome level 7. SABIC (2003). ‘Meet the ‘omics’’, AgBiotech InfoSource, 81, pp. 1-2.. There are many established databases used for the collection and analysis of associated data and information relating to these disciplines. Sequenced genomes can be accessed from sites such as the National Center for Biotechnology Information or Ensembl. As scientific research has expanded over time the scope of these ‘omics’ has also widened. Influence and Impact Natalie Bolton The importance of understanding an entire system is evident in the influence and impact systems biology has already had on understanding a variety of biological mechanisms, and in the quantity of developments resulting from research involving systems biology. Research based on understanding systems has impacted a wide range of scientific areas, some of which are described here: 'Modelling Systems' Systems can be modelled and simulated on a number of levels: *Simulation of cellular processes within the cell *Simulation of cell development *Simulation of entire organs *Simulation of an entire organism Yao, T. (2002) ‘Bioinformatics for the genomic sciences and towards systems biology. Japanese activities in the post-genome era’, Progress in Biophysics and Molecular Biology, 80(1-2), pp. 23-42. An example of this is the simulation of signal transduction pathways, which often involve large numbers of molecules and a complex web of interactions and reactions. They can be studied computationally through the use of kinetic models: Reaction equations and parameters can be set, and the pathway can be simulated to analyse how it reacts to various stimuli Babu, C.V.S., Song, E.J. and Yoo, Y.S. (2006) ‘Modeling and simulation in signal transduction pathways: a systems biology approach’, Biochimie, 88(3-4), pp. 277-283.. 'Understanding Complex Diseases/Pathology' Many diseases can be studied at a system level in order to better understand their mechanisms and how they progress. For example, cell shape in cancer can be studied using fractal analysis – irregular structures can be characterized and distinguished, such as differentiating between benign and malignant neoplasms Bizzam, M., Giuliani, A., Cucina, A., D’Anselmi, F., Soto, A.M. and Sonnenschein, C. (2011) ‘Tractal analysis in a systems biology approach to cancer’, Seminars in Cancer Biology, 21(3), pp. 175-182.. Another example is metabolic syndrome: Systems biology can be used to study interactions between the genes involved, the environmental impact on such genes, and lipodomic profiles of plasma membranes Orešič, M. (2010) ‘Systems biology strategy to study lipotoxicity and the metabolic syndrome’, Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids, 1801(3), pp. 235-239.. Heart failure is another candidate for benefitting from a systems-based approach, as the numerous biochemical pathways and networks involved in each clinical phenotype of the condition can be identified Louridas, G.E. and Lourida, K.G. (2011) ‘A conceptual paradigm of heart failure and systems biology approach’, International Journal of Cardiology, In press, corrected proof.. 'Understanding Infectious Diseases' Systems biology can be used to understand the numerous systems involved in infectious disease. In this case it is useful to understand the systems of the host and the pathogen. Understanding these can help to discover the pathogenesis of the infection, and can identify therapeutic targets. An example of this the use of haplo-insufficiency screens to select new drug targets to treat fungal infections Santamaría, R., Rizzetto, L., Bromley, M., Zelante, T., Lee, W., Cavalieri, D., Romani, L., Miller, B., Gut, I., Santos, M., Pierre, P., Bowyer, P. And Kapushesky, M. (2011) ‘Systems biology of infectious diseases: a focus on fungal infections’, Immunobiology, 216(11), pp. 1212-1227.. 'Developing Biotechnology' Understanding an entire system can identify niches in organisms that can be utilised in biotechnology. For example, metabolic flux analysis and complete genome sequencing has been used to study the metabolic pathways of Corynebacterium glutamicum, allowing development of its use in the production of amino acids Wendisch, V.F., Bott, M., Kalinowski, J., Oldiges, M. And Wiechert, W. (2006) ‘Emerging Corynebacterium glutamicum systems biology’, Journal of Biotechnology, 124(1), pp. 74-92.. Understanding plant systems through the use of systems biology can also unlock their potential in synthetic biology, for example the synthetic production of plant-derived compounds for pharmacological use Zurbriggen, M.D., Moor, A. And Weber, W. (2012) ‘Plant and bacterial systems biology as platform for plant synthetic bio(techno)logy’, Journal of Biotechnology, In press, corrected proof.. 'Drug Development' Another impact has been on drug development. Human genome sequencing has provided a base from which to develop personalised medicines, whilst the sequencing of microbial genomes presents scope for identification of novel drug targets to treat infectious disease . Cancer signalling networks can be modelled and studied to develop new therapies. For example, modelling of the ErbB network recently identified ErbB3 as a drug target for cancer therapy. The research has led to development of a monoclonal antibody against ErbB3, which has reached phase II clinical trials Prasasya, R.D., Tian, D. And Kreeger, P.K. (2011) ‘Analysis of cancer signalling networks by systems biology to develop therapies’, Seminars in Cancer Biology, 21(3), pp. 200-26.. In the field of anti-epileptic drugs, the “Systems Biology of Epilepsy Project” is combining numerous data types to identify genes expressed in seizure zones of the epileptic brain. These genes could be targets of future therapies Margineanu, D.G. (2012) ‘Systems biology impact on antiepileptic drug discovery’, Epilepsy Research, 98(2-3), pp. 104-115.. Future Outlook Craig Bradford The study and simulation of entire systems will allow us to predict, with far greater accuracy, the effects of genetically modifying micro-organisms, allowing us to tailor-make organisms for whatever purposes we require. The impact such a leap forward could have upon the global economy is staggering – drugs could be tailored specifically to particular strains of pathogens by identifying and then obviating their drug resistance mechanisms, food (in the form of single-cell protein) could be grown with a specific nutrient balance in order to provide new staple food sources for people all over the world and biofuels could be produced far more efficiently than is currently possible – as a start Weston, A.D., Hood, L. (2004) 'Systems Biology, Proteomics, and the Future Health Care: Toward Predictive, Preventative, and Personalised Medicine', Journal of Proteome Research, 2, pp. 179-196. Andrianantoandro, E., Basu, S., Karig, D.K, Weiss, R. (2006) 'Synthetics Biology: new engineering rules for an emerging dicipline', Molecular Systems Biology 2006.0028, doi:10.1038/msb4100073.. Further examples could include the capability for spacecraft to produce their own food and fuel, allowing for much longer space missions, and reducing the cost of projects like the International Space Station due to the lower resupply needs that would come with the implementation of such technology. Of course, to get this far, it will be necessary to continue the development of high-throughput genetic sequencing and analysis techniques, and computer processing power will need to increase substantially as well, particularly for the purpose of simulating entire cells . Additionally, there will need to be worldwide standardisation of data collection and processing. This last point is, in a way, already happening – with the increased usage of tools like ORFfinder, FramePlot, BPROM, BLAST, RSAT, ClustalIW, TOMTOM, and databases like the Gene Expression Omnibus (GEO), the formats and usage of data is becoming more and more standardised. With this standardisation, scientists everywhere will be able to use data from a number of sources, without having to convert data in any way. As worldwide Internet infrastructure advances, the exchange of this data will become much more rapid – while some nations have very good infrastructure, allowing them to handle the large volumes of data required by system-scale projects, a majority are some way behind, for various reasons. Once these have advanced, it will allow much more rapid dissemination of data, which, as with processing capacity, will allow much more rapid analysis of data and will help increase the rate of advancement in the field of systems biology. Concluding Remark In conclusion, understanding an entire system is important because it will allow us to predict the effects of stimuli on systems, and thereby manipulate them to our benefit. Bibliography Links Institute for Systems Biology homepage: https://www.systemsbiology.org/ National Center for Biotechnology Information: http://www.ncbi.nlm.nih.gov/ Ensembl: http://www.ensembl.org/index.html ORFfinder: http://www.ncbi.nlm.nih.gov/projects/gorf/ FramePlot: http://www0.nih.go.jp/~jun/cgi-bin/frameplot.pl BPROM: http://www.bio.net/bionet/mm/bio-www/2003-January/001122.html, http://linux1.softberry.com/berry.phtml BLAST: http://blast.ncbi.nlm.nih.gov/ RSAT: http://rsat.ulb.ac.be/ ClustalIW: http://www.ebi.ac.uk/Tools/msa/clustalw2/ GEO: http://www.ncbi.nlm.nih.gov/geo/ Editing ''Lisa Buddrus '' Background/Logo Source: http://pubs.acs.org/cen/images/8120/8120cover.JPG Category:Browse